Browsing by Subject "Asymmetric synthesis"
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Item ASYMMETRIC SYNTHESIS OF AMINO COMPOUNDS BY USING CHIRAL N-PHOSPHONYL IMINES(2010-12) Ai, Teng; Li, Guigen; Mayer, Michael F.; Fuertes, Michael J.The great demand in life science for new molecules of biological and medicinal importance has led to an extreme significance of the development of synthetic methodologies. The asymmetric synthesis of chiral amines has long been a popular and challenging research area because chiral nitrogen-containing compounds are widely distributed in nature and many biologically important molecules. For the synthesis of chiral nitrogen-containing carbon frame works using imines as electrophiles is the most promising and convenient route. In the past two decades, chiral auxiliary based imines has drawn great attention in the asymmetric synthesis of a broad range of chiral amines such as natural products, pharmaceutical ingredients etc. In this dissertation, the development of new class of chiral phosphonyl imines and their applications in chiral amine synthesis are reported. In the first part, new chiral N-phosphonyl imines with different structure modifications were designed and synthesized. New methods were developed to reduce the reaction times and improve the reaction yields. In Particular, N-phosphonyl ketimines were obtained in good yields with the employment of a concise method which provide a general solution to the synthesis of phosphonyl imines. Six asymmetric nucleophilic addition reactions of these phosphonyl imines were discussed in the following part. Good to excellent yields and diastereoselectivities were obtained in all the cases. The resulting or amino containing compounds are extremely valuable building blocks in organic chemistry. Moreover, different coordination patterns between phosphonyl imines and nucleophiles in transition state were proposed to explain the stereochemistry of the products.Item Development of new synthetic methodologies(Texas Tech University, 2001-12) Kim, Sun HeeSeveral new synthetic methodologies of chemically and biologically importance are described in this dissertation. These include electrophilic aminohalogenation, electrophilic diamination, Baylis-Hillman type bond formations and Mukaiyama aldol type reactions. These reactions are for either carbon-nitrogen or carbon-carbon bond formations and can result in multifunctionalized products. Efficient nitrogen/halogen sources are studied as electrophiles for electrophilic aminohalogenation and diamination. Transition metals or their complexes with ligands are utilized as catalysts to control the regio- and stereoselectivity. A/-Arylsulfonyl-A/-chloroaziridinium ions are confirmed as novel intermediates to exist in electrophilic additions of alkenes. The resulting haloamine and vicinal diamine derivatives have been converted into aziridines and a,p-differentiated amino acids. Baylis-Hillman type adducts are obtained by the treatment of aldehydes with acetylenic carbonyl compounds in the presence of TiCI4 as the Lewis acid promoter. The reaction proceeds through the formation of halo aldol adducts. These adducts have been isolated in good yields, which extends the application of classical aldol reaction. A similar reaction system has also been applied for new C=C bond formations. Asymmetric versions of Baylis-Hillman type reactions and aldol reactions have been systematically studied. New chiral auxiliaries are employed to direct the chirality of products. Chiral sulfinimines are successfully utilized as electrophilic acceptors for the asymmetric synthesis of multifunctionalized Baylis- Hillman adducts, p-halo, p-monosubstituted, and p,p-disubstituted Baylis-Hillman olefines. Among these products, a-alkylidene p-amino acids have been found to serve as novel leads for the design of anf/-cancer drugs by NIH. Finally, novel synthesis of oxazaborolidine auxiliaries is demonstrated in which unique solutionto- solid and solid-to-solid techniques are applied. For the later case, no solvent is required; therefore, the reaction is environmentally friendly.Item Electrophilic trapping of enolates in tandem reaction processes and (1,3-diketonato)metal templates for asymmetric catalysis(2004) Bocknack, Brian Matthew; Krische, Michael J.The discovery of methods for the catalytic generation of enolates in the presence of suitable electrophilic partners has led to the development of several effective strategies for the tandem formation of multiple bonds. Typically, enones have been utilized as latent enolates in these tandem processes. For instance, catalytic enone hydrometalation in the presence of an aldehyde or ketone partner allows for the formation of reductive aldol products. Similarly, the presence of an α,β-unsaturated carbonyl acceptor has been shown to give products of a reductive Michael reaction. The historical development of these tandem conjugate reduction–electrophilic trapping processes is reviewed herein. Enolate generation through catalytic enone carbometalation has also been employed as a strategy in the development of novel transformations. This approach has been used to devise an efficient protocol for the desymmetrization of enone-dione substrates via rhodium-catalyzed conjugate addition–enolate trapping. Using this methodology, four contiguous stereocenters can be established in a single manipulation, with high levels of both relative and absolute stereocontrol. This technique has provided a concise route to seco-B-ring steroids possessing a 14-hydroxy cis fused C-D ring junction, as found in naturally occurring cardiotonic steroids derived from digitalis purpurea. Numerous stereogenic processes are catalyzed by transition metal complexes of 1,3-diketonates. Despite this fact, the development of enantioselective variants using chiral (1,3-diketonato)metal templates has been slow. Progress toward the development of a novel family of chiral 1,3-diketonate ligands for asymmetric catalysis is described. These ligands, which all arise from acylation of a common pseudo-planar chiral monoketone precursor, have been used to form a variety of (1,3-diketonato)metal complexes. Additionally, the first known examples of C2-symmetric bis(1,3-diketonate) ligands have been obtained through extension of this modular approach to ligand synthesis. Although highly enantioselective catalytic transformations employing these new (1,3-diketonato)metal complexes have not yet been realized, the knowledge gained from the intial studies presented herein establishes a foundation for future development.Item Enones and enals as latent enolates in catalytic C-C bond forming processes : total synthesis of (-)-paroxetine (Paxil®)(2007-05) Koech, Phillip Kimaiyo, 1974-; Krische, Michael J.Enolates constitute one of the most commonly utilized intermediates in synthetic organic chemistry. However, the regioselective generation of enolates remains a challenge, especially for non-symmetric ketones possessing identical degrees of substitution at the α-positions. Our research has shown that regioselective enolate generation can be achieved by the activation of enones and enals with either 1) nucleophilic phosphine catalysis or 2) transition metal catalysis to generate enolates regioselectively. These enolates can be subsequently trapped with electrophiles. Using nucleophilic phosphine catalysis we have developed the first method for the α-arylation of enones, enals, and nitroalkenes using bismuth(V) reagents. This phosphine-catalyzed arylation methodology is mild in that a strong base is not required. Additionally, the products of this reaction are easily elaborated to complex molecules. This method has been strategically applied in a concise formal and enantioselective total synthesis of the blockbuster antidepressant (-)-paroxetine (PAXIL®). In transition metal catalysis, we have used enantioselective Cu-catalyzed conjugate addition of Grignard reagents to enones to provide magnesium enolates, which can be arylated using bismuth(V) reagents to furnish products of vicinal difunctionalization of enones. These products are obtained in modest to good yields with complete control of both relative and absolute stereochemistry. Another method for regioselective enolate generation is the Rh-catalyzed hydrogenation of enones and enals. Using this method we have developed a reaction that involves addition of metalloaldehyde enolates to ketone acceptors to afford aldol products. This is the first catalytic direct addition of transition metal enolates to ketones.Item Enones and enals as latent enolates in catalytic C-C bond forming processes: total synthesis of (-)-paroxetine (Paxil®)(2007) Koech, Phillip Kimaiyo; Krische, Michael J.Item New chiral bis(oxazoline) ligands for asymmetric catalysis(2005) Le, Cong-Dung Thi; Pagenkopf, Brian L.Item Novel olefin additions and carbon-carbon bond forming reactions(Texas Tech University, 2006-05) Timmons, James CodyAs the nation's population and life expectancy continue to increase, the development of new molecules of biological and medicinal importance has moved to the forefront of modern science. Central to this theme is the development of new synthetic strategies for the construction of these molecules. In particular, the transformation of simple, readily available starting materials into highly functionalized synthetic intermediates is among the most important challenges facing the organic chemist today. In this dissertation, several new methodologies are reported for the synthesis of novel amines, alcohols, ethers, and related compounds. The first class of reactions deals with the oxidation of olefins to afford vicinal diamines. Such compounds are of great importance due to their similarity to amino acids. However, with the presence of an additional amine group, these compounds can significantly complement natural amino acids in a variety of roles. In particular, peptide studies and catalysis research can greatly benefit from the ready availability of vicinal diamnes. The second class of reactions reported herein involves the construction of new carbon-carbon bonds. Halo aldol, Mannich, and Morita-Baylis-Hillman reactions are reported that are significantly more functionalized than their non-halogenated counterparts, thus making them more useful building blocks. The majority of these reactions were rendered asymmetric. In addition, the work has been extended to include the preparation of 5- and 6-membered oxygen and nitrogen heterocycles.Item Novel olefin additions and carbon-carbon bond forming reactions(2006-05) Timmons, James C.; Li, Guigen; Birney, David M.; Headley, AllanAs the nation's population and life expectancy continue to increase, the development of new molecules of biological and medicinal importance has moved to the forefront of modern science. Central to this theme is the development of new synthetic strategies for the construction of these molecules. In particular, the transformation of simple, readily available starting materials into highly functionalized synthetic intermediates is among the most important challenges facing the organic chemist today. In this dissertation, several new methodologies are reported for the synthesis of novel amines, alcohols, ethers, and related compounds. The first class of reactions deals with the oxidation of olefins to afford vicinal diamines. Such compounds are of great importance due to their similarity to amino acids. However, with the presence of an additional amine group, these compounds can significantly complement natural amino acids in a variety of roles. In particular, peptide studies and catalysis research can greatly benefit from the ready availability of vicinal diamnes. The second class of reactions reported herein involves the construction of new carbon-carbon bonds. Halo aldol, Mannich, and Morita-Baylis-Hillman reactions are reported that are significantly more functionalized than their non-halogenated counterparts, thus making them more useful building blocks. The majority of these reactions were rendered asymmetric. In addition, the work has been extended to include the preparation of 5- and 6-membered oxygen and nitrogen heterocycles.